Alkylation of γ‐Azaproline Creates Conformationally Adaptable Proline Derivatives for pH‐Responsive Collagen Triple Helices
Matthew R. Aronoff, Jasmine Egli, Adeline Marie Schmitt, Helma Wennemers
Abstract
Abstract C γ ‐substituted proline derivatives are valuable tools for developing functionalized collagen peptides for biological and materials investigations, yet the stereochemistry at C γ can produce undesired steric or stereoelectronic constraints. Alkylated γ‐azaproline (γ‐azPro) derivatives are proline mimetics that lack a stereogenic center at the γ‐position of the ring and can thus utilize the invertibility of nitrogen to adapt their conformation. NMR spectroscopic analyses and DFT calculations highlighted how alkylated γ‐azPro derivatives are conformationally dynamic and adopt conformational preferences through ring pucker flip along with nitrogen inversion. Lastly, incorporation of alkylated γ‐azPro into collagen peptides produced functionalized pH‐responsive triple helices with similar thermal stabilities, regardless of their placement in the Xaa or Yaa position within the characteristic Xaa‐Yaa‐Gly repeating unit of collagen peptides.